This project intends to design strategies that may ultimately contribute to long term control or even cure of HIV-1 infection. It will test hypotheses about mutational patterns of resistance to specific new drugs, drug susceptibility and replicative fitness phenotypes of drug-selected mutants, and the pathophysiology of failure of combination regimens and HIV's latent reservoir. It will also develop improved clinical monitoring for virus resistance and test a novel treatment strategy based on these hypotheses. The specific aims of this project are: 1) To define the resistance genotypes and phenotypes selected in vivo during failure of combination regimens including either a PI, an NNRTI, or abacavir and to test cross-resistance of amprenavir- and abacavir-selected mutants. 2) To perform and develop in vitro characterizations of replicative fitness of mutant HIV-1s and the latent reservoir of HIV-1 relevant to the pathophysiology of virologic rebound during and after combination therapy. 3) To develop improved methods and strategies for clinical monitoring of antiretroviral resistance. 4. To perform a pilot, randomized clinical trial of proactive switching of antiretroviral combinations with or without intensive viral load monitoring versus the current standard strategy of changing drugs only after sustained virologic rebound is confirmed.